Efficacy and safety of once-weekly basal insulin versus once-daily basal insulin in patients with type 2 diabetes: A systematic review and meta-analysis

Background: Once-weekly insulin is expected to improve treatment compliance and durability and lead to better glycemic control. Several clinical trials on once-weekly insulin have recently been published. We conducted a systematic review and meta-analysis to investigate the efficacy and safety of once-weekly insulin versus once-daily insulin in type 2 diabetes (T2D). Methods: The following databases were searched for studies: PubMed, EMBASE, and Cochrane library (From January 1, 1946 to May 9, 2023). All randomized trials comparing weekly versus daily insulin in T2D were eligible for inclusion. Data analysis was performed using STATA 17.0 software (Stata Corporation, College Station, TX). The main outcomes and indexes included reduction in Hemoglobin A1c (HbA1c), fasting plasma glucose and bodyweight, proportion of patients achieving HbA1c < 7%, time-in-range 70 to 180 mg/dL and adverse events. Results: This systematic review and meta-analysis included 7 randomized controlled studies involving 2391 patients (1347 receiving 1-week insulin and 1044 receiving 1-day insulin). Once-weekly insulin was not inferior to once-daily insulin in HbA1c change [estimated treatment difference (ETD) = −0.05; 95% confidence intervals (CI): −0.14 to 0.04), HbA1c < 7% (odds ratio = 1.14; 95% CI: 0.87–1.50), fasting plasma glucose (ETD = 0.09; 95% CI: −0.19 to 0.36) and body weight loss (ETD = 0.27; 95% CI: −0.36 to 0.91). In terms of time-in-range 70 to 180 mg/dL, weekly insulin was superior to daily insulin (MTD = 3.84; 95% CI: 1.55–6.08). Icodec was associated with higher incidence of all adverse events (odds ratio = 1.20; 95% CI: 1.03–1.48; P = .024), but did not result in high risk of serious and severe adverse events. Moreover, icodec and Basal Insulin Fc did not result in higher incidence of hypoglycemia compared with insulin daily. Conclusion: Our meta-analysis found that insulin weekly was well tolerated and effective for glycemic control. Once-weekly insulin was not inferior to once-daily insulin in both efficacy and safety in T2D.


Introduction
The increasing number of people with diabetes worldwide not only poses a serious threat to human health, but also brings huge economic burden to society.As one of the 2 major drugs in the treatment of diabetes (insulin and oral hypoglycemic drugs), insulin has been a great boon for hundreds of millions of diabetic patients who need insulin treatment.Treatment of type 2 diabetes (T2D) often requires the addition of basal insulin as the disease progresses if the patient does not meet blood glucose targets. [1]Compared with oral hypoglycemic drugs, insulin needs to be injected, thereby bringing inconvenience to many patients.According to the currently approved clinical application of insulin analogues, patients with diabetes often need to be injected at least once a day, possibly 2 to 4 times, and may also need to be combined with oral drugs for treatment, which mean complex treatment strategies and tedious self-blood glucose management. [2][5] Although once-daily basal insulin analogues have solved some of these problems, long-term daily injection therapy is still a heavy burden on patients.Thus, reducing the number of injections may increase the acceptance and adherence of patients with T2D to insulin therapy, ultimately leading to improve blood sugar control.[8][9] With the successful marketing of "once a week" glucagon-like peptide-1 receptor agonist (GLP-1RA) weekly formulations, people are full of expectations for onceweekly basal insulin.Recent clinical studies have found a similar effect with once-weekly basal insulin. [10,11]At present, the current research of basic insulin preparation mainly includes Basal Insulin Fc (BIF) and icodec 2 types.Randomized controlled studies of these 2 types of insulin show some promise to change the treatment landscape.To more fully evaluate the role of weekly basal insulin, we conducted a meta-analysis that pooled all current randomized controlled studies comparing the efficacy and safety of once-weekly basal insulin to oncedaily basal insulin in patients with T2D.

Methods
This study was registered in the PROSPERO database (CRD42023425651) and was conducted according to the preferred reporting project for systematic review and meta-analysis (PRISMA) statement. [12]The objective of this meta-analysis was to compare the efficacy and safety of once-weekly basal insulin with once-daily basal insulin in T2D.

Eligibility criteria
The study was independently screened by 2 authors.The inclusion criteria used to select studies in this meta-analysis were: Patients clinically diagnosed with T2D; Prospective Phase II or III randomized clinical trials comparing once-weekly basal insulin with once-daily basal insulin in T2D; Studies reporting at least one of the following results: reduction in hemoglobin A1c (HbA 1c ), fasting plasma glucose (FPG) and bodyweight, proportion of patients achieving HbA 1c < 7%, time-in-range 70 to 180 mg/dL (TIR) and adverse events (AEs).Exclusion criteria: Patients clinically diagnosed with type 1 diabetes mellitus; Nonrandomized controlled studies, basic studies, retrospective studies, case reports, duplicate publications, and studies for which relevant data cannot be extracted.

Literature search
Randomized Control Trials comparing once-weekly insulin icodec versus once-daily insulin, in patients with T2D, were identified by computerized search of PubMed, Embase and Cochrane Library (From January 1, 1946 to May 9, 2023), using the following search terms: once-weekly insulin, oncedaily insulin, Icodec, weekly basal Insulin Fc, BIF and type 2 diabetes.The detailed search strategy is as described in the Supplemental Digital Content, http://links.lww.com/MD/L249.There are no language or date restrictions on searches.If overlapping data exists, the most complete and updated report is selected for inclusion in this meta-analysis.Manually review references from all eligible studies to find other relevant studies.

Study selection and data extraction
Two experienced system reviewers independently screen records for eligibility.Any disagreements are resolved by consulting a third reviewer.Browse titles and abstracts to complete an initial selection, then browse the full text of potentially eligible articles, and select eligible articles based on preestablished criteria.Data were extracted using a prespecified data collection form, which included baseline characteristics, sample size and interventions used, changes in the number of assessable patients HbA 1c change, HbA 1c < 7%, FPG, body weight loss, TIR, AEs, etc. Two system reviewers independently extract relevant data and resolve differences by consulting a third reviewer.When multiple articles contained overlapping patient series, we prioritized extraction of outcome data from the major articles with the largest sample size for early outcomes and the articles with the longest follow-up time for late outcomes.

Risk of bias
Two of our reviewers independently applied the Cochrane Collaboration tool to assess the quality of included trials in the following areas: random sequence generation, assignment hiding, blinding, incomplete results data, and selective results reporting. [13]Differences were resolved by consulting a third reviewer.

Statistical analysis
Data were analyzed using STATA 17.0 software (Stata Corporation, College Station, TX).HbA 1c change, FPG, bodyweight and TIR were reported as estimated treatment difference (ETD) and corresponding 95% confidence intervals (CI).Proportion of patients achieving HbA 1c < 7% and AEs reported as odds ratio (OR) and 95% CI.Due to the heterogeneity among different study designs, methods and populations, in order to make the results more reliable, the random effects model was used in this study to combine relevant data.In addition, the Cochrane Q test and I 2 test were used to evaluate heterogeneity among the studies.I 2 higher than 50% is considered to be highly heterogeneous. [14,15]Publication bias was assessed by funnel plot and Egger regression test. [16]If heterogeneity was found, meta regression was performed to further explore the source of heterogeneity.Subgroup analyses of insulin type, duration of treatment, and presence or absence of basal insulin therapy were planned.
Statement: Our meta-analysis does not address the subject's life, health, dignity, privacy, and other related issues.All analyses were based on previous published studies, thus no ethical approval or patient consent was required.

Risk of bias assessment
Since all studies included were randomized, selection and loss bias were minimized.Most studies used central randomization for random allocation, and only 1 trials did not mention the method of allocation hiding. [17]The main source of bias is that blindness was not used in most of the trials.A certain risk of bias may arise from the fact that blood glucose was not assessed blind in the study of Frias et al [11] (Table S1, Supplemental Digital Content, http://links.lww.com/MD/K905).

Adverse events.
][19][20][21] Due to the different types of adverse events reported for icodec and BIF, the data for icodec and BIF were combined separately (Table 2).Results showed that icodec was associated with higher incidence of all adverse events (OR = 1.20; 95% CI: 1.03-1.48;P = .024),but did not result in higher risk of serious and severe adverse events.In level 1 hypoglycemia, level 2 or 3 hypoglycemia, injection-site reaction, hypersensitivity event, and any adverse event probably or possibly related to basal insulin, there was no statistical difference between Icodec and once-daily insulin.On the other hand, there was no statistical difference between BIF and once-daily insulin in terms of level 1 hypoglycemia, nocturnal level 1 hypoglycemia, and level 2 hypoglycemia.However, BIF was associated with lower nocturnal level 2 hypoglycemia (OR = 0.68; 95% CI: 0.47-0.98;P = .036).

Subgroup analysis
3.4.1.Insulin type.In HbA 1c Changes, the Icodec subgroup showed superior efficacy compared with once-daily insulin, but there was no statistical difference between the 2 groups in the BIF subgroup.There was no statistical difference in FPG among the icodec subgroups, but it was inferior to once-daily insulin in BIF.In addition, in HbA 1c < 7%, icodec and BIF were comparable to once-daily insulin.Interestingly, in terms of weight loss, the 2 subgroups had opposite benefits, with icodec being inferior to daily insulin and BIF being superior to daily insulin (Table 3 and Figure S1-S5, Supplemental Digital Content, http://links.lww.com/MD/K908, http://links.lww.com/MD/K909,http://links.lww.com/MD/K910, http://links.lww.com/MD/K911,http:// links.lww.com/MD/K912).

Treatment duration.
In HbA 1c changes and HbA 1c < 7%, there was no statistical difference among the 3 subgroups.Moreover, there was no statistical difference in FPG for the 16-week and 26-week subgroups, but once-weekly insulin was inferior to once-daily insulin in the 32-week subgroup.Moreover, in terms of weight loss, there was no statistical significance in the 16-week treatment subgroup; the 26-week subgroup showed a superiority of weekly insulin, while the 32-week subgroup showed an inferiority of weekly insulin.On the contrary, there was no statistical significance in the 26-week treatment subgroup in TIR, but the 16-week subgroup showed a superiority of weekly insulin.

Basal insulin-treated.
There were no significant differences in HbA 1c changes, HbA 1c < 7%, FPG, weight loss and TIR in both of 2 subgroups.

Meta regression, sensitivity analysis, and publication bias
The results of meta regression suggested that the heterogeneity of most outcomes was due to insulin type (Table S2, Supplemental Digital Content, http://links.lww.com/MD/K906).Sensitivity analysis by removing 1 study at a time found that   S3, Supplemental Digital Content, http://links.lww.com/MD/K907).

Discussion
Insulin is an indispensable treatment in T2D.Although oral hypoglycemic drugs provide great convenience, with the development of the disease, oral hypoglycemic drugs alone may no longer be able to effectively control blood glucose, and then additional insulin is needed to strengthen blood glucose control [1] Diabetes is a chronic disease that requires long-term medication or insulin injections to control blood glucose and prevent complications.The inconvenience of frequent injections reduces patient compliance, as well as quality of life.Recently published clinical trials have shown promise in reducing the frequency of insulin injections to once a week.Therefore, we summarized all current randomized controlled trials and conducted a meta-analysis comparing the efficacy and safety of onceweekly insulin versus once-daily insulin.The results showed that once-weekly insulin was not inferior to insulin daily for T2D in HbA 1c changes, HbA 1c < 7%, FPG and weight loss.Notably, this non-inferior glycemic effect was not associated with increased risk of hypoglycemia.In terms of TIR, weekly  insulin was superior to daily insulin.Our results demonstrated that once-weekly insulin was similar to once-daily insulin in terms of hypoglycemic risk, suggesting that once-weekly insulin was not inferior to once-daily insulin in terms of efficacy or safety.A previous meta-analysis of 3 trials found that onceweekly Insulin Icodec was associated with a small reduction in HbA 1c , as well as higher Time with Glucose in Range.However, this meta-analysis included only 453 patients. [22]Our metaanalysis included the recently updated Phase 2 and III clinical trials involving a total of 2391 patients, and conducted a subgroup analysis to explore the impact of prior insulin-treated, insulin type, and treatment duration on the outcome.Therefore, our results are more reliable and instructive.Icodec is a basal insulin analogue whose strong, reversible binding to albumin and reduced insulin receptor affinity to slow clearance, leading to the formation of a circulating albumin binding library for insulin icodec.[25] ONWARDS 2 and ONWARDS 4 are the first 2 Phase III trial to publish clinical data showing that icode is safe and efficacious in patients with T2D suboptimally controlled with basal insulin. [10,21]In these studies, icodec showed non-inferior glycemic control compared with insulin glargine as measured by HbA 1c change from baseline to study end point.A previous, double-blind, randomized controlled trial of insulinnaive T2D patients showed similar results.This trial was more rigorous with the fasting blood glucose target. [17]In addition, Novo Nordisk conducted ONWARDS1, 3, and 5 to evaluate the efficacy and safety of icodec in insulin-naive patients with T2D. [26]However, as the full data of these 3 trials have not been published, they were not included in our meta-analysis.The results of these 3 studies indicate that icodec was not inferior to insulin daily in reducing HbA 1c , which was consistent with the results of our meta-analysis.BIF, the second once-weekly insulin in development, is a novel fusion protein that binds a single chain insulin variant to the Fc domain of human immunoglobulin  G. [27,28] Unlike icodec, BIF has a longer half-life of 17 days.In 2 Phase II trials, BIF was administered using mg steps instead of international units of insulin to help establish clinically correct mg to international units conversion factors in all relevant populations.Phase II clinical trials have shown that BIF is safe and effective in insulin-naive and insulin-treated patients. [11,20]ecause of the long half-life, icodec and BIF also take longer to reach steady state.Thus, in insulin-treated patients, both icodec and BIF were given a loading dose, based on the results of the Phase 1 study, to reach homeostasis concentrations more quickly and minimize transient hyperglycemia.Bajaj et al [18] evaluated the efficacy and safety of dose and unloaded dose icodec versus once-daily insulin in insulin-treated patients.
The results showed that TIR changes were greater in the loaded dose group than in the unloaded dose group (15.4% vs 8.6%) and there was no increased risk of hypoglycemia.Some limitations should be taken into account when interpreting our results.In HbA 1c , FPG, body weight loss, TIR and HbA 1c < 7% of the analyses, there was some degree of statistical heterogeneity, as measured by I 2 statistics.Therefore, we conducted meta regression to explore the source of heterogeneity.The results showed that the heterogeneity was mainly due to insulin type.In order to better analyze heterogeneity, subgroup analysis was performed.Subgroup analysis of insulin type found icodec was superior to BIF in HbA1c change, FPG, and HbA 1c < 7%, but was inferior to BIF in weight loss.Upon further review of the included studies, it was found that the reason for this difference may be that the fasting glucose target of degludec in Frias et al [11] study was ≤ 5.6 mmol/L, which was more stringent than that of BIF, while the fasting glucose target of icodec was consistent with that of once-daily insulin.In any insulin therapy, due to its physiological role as an anabolic hormone that promotes the uptake and storage of glucose by cells, there is always an inherent delicate balance between achieving good blood sugar control, hypoglycemia, and weight change.So this difference could partly explain why icodec outperformed BIF in blood glucose control and the opposite in weight loss.In the subgroup analysis of treatment duration, the 32 week subgroup included only Frias et al, [11] so we found a similar situation where BIF was inferior to insulin daily in terms of FPG.In addition, to assess the impact of prior insulin therapy, a subgroup analysis was performed to explore the difference between weekly doses of insulin in initial and treated patients.The results showed that there were no significant differences in HbA 1c , HbA 1c < 7%, FPG, body weight loss and TIR between the 2 subgroups.
In terms of adverse events, icodec was associated with higher risk of all adverse events, but not more serious adverse events.In addition, icodec did not lead to a more severe incidence of hypoglycemia, nor did level 2 or 3 hypoglycemia.No level 3 hypoglycemic events due to icodec were observed in other studies except for 1 level 3 hypoglycemic event in the study by Rosenstock et al [17] and 4 in the study by Mathieu et al [21] .On the other hand, BIF did not result in more severe hypoglycemic events.Interestingly, BIF reduced the incidence of nocturnal level 2 hypoglycemia.As mentioned earlier, Frias et al [11] fasting glucose targets for degludec were more stringent than those for BIF.Our meta-analysis found that icodec and BIF were safe and feasible compared to once-daily insulin.
[31] Therefore, the combination of weekly insulin and weekly GLP-1RA is a promising strategy.Future studies could explore the feasibility of this combination.
There are some limitations to our study.First of all, most experiments are open label designs.Secondly, some results were highly heterogeneous, but we conducted meta regression and subgroup analysis to fully explore the sources of heterogeneity and used a random effects model to reduce bias.Third, insulin schedules and fasting glucose targets were not identical across trials, which could lead to some bias.

Conclusion
The results of this meta-analysis of 7 randomized controlled trials (2391 participants) showed that once-weekly insulin was not inferior to once-daily insulin for T2D in HbA 1c change, HbA 1c < 7%, FPG and weight loss.In terms of TIR, once-weekly insulin was superior to once-daily insulin.Moreover, the incidence of hypoglycemia was similar and the safety was comparable.Therefore, once-weekly insulin is safe and feasible in T2D.

Figure 2 .
Figure 2. Assessment of HbA1c change.The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI).Due to the heterogeneity among different study designs, methods and populations, a random effects model was used.CI = confidence intervals, ETD = estimated treatment difference, HbA1c = hemoglobin A1c.

Figure 3 .
Figure 3. Assessment of fasting plasma glucose.The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI).Due to the heterogeneity among different study designs, methods and populations, a random effects model was used.CI = confidence intervals, ETD = estimated treatment difference.

Figure 4 .
Figure 4. Assessment of body weight loss.The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI).Due to the heterogeneity among different study designs, methods and populations, a random effects model was used.CI = confidence intervals, ETD = estimated treatment difference.

Figure 5 .
Figure 5. Assessment of HbA 1c < 7%.The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI).Due to the heterogeneity among different study designs, methods and populations, a random effects model was used.CI = confidence intervals, ETD = estimated treatment difference, HbA1c = hemoglobin A1c.

Figure 6 .
Figure 6.Assessment of time-in-range 70-180 mg/dL.The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI).Due to the heterogeneity among different study designs, methods and populations, a random effects model was used.CI = confidence intervals, ETD = estimated treatment difference.

Table 1
Characteristics of included studies.

Table 2
Results of adverse events.